OBJECTIVES: Paradoxical thromboembolism across a patent foramen ovale (PFO) may be involved in the pathogenesis of cryptogenic strokes. We tested the feasibility and the clinical usefulness of an early screening for PFO combining different ultrasound techniques in patients with acute cerebral ischemia of undetermined cause. METHODS: Consecutive patients with acute ischemic stroke or transient ischemic attack with undetermined cause were selected. Contrast-enhanced transcranial Doppler ultrasound (c-TCD) for detection of right-to-left shunt was performed on admission. Patients with right-to-left shunt on c-TCD underwent contrast-enhanced transesophageal echocardiography (c-TEE) and/or contrast-enhanced transthoracic echocardiography (c-TTE) for PFO confirmation. We tested the feasibility of this ultrasound algorithm in patients with acute cerebral ischemia, as well as its impact on further treatment decision. RESULTS: Over 30 months, we admitted 154 of 674 (23%) patients with undetermined stroke cause. Right-to-left shunt was detected by c-TCD in 76 of 148 (51%) patients. Of them, five of 76 (7%) patients dropped out of the study, whereas 10 of 76 (13%) could not perform a c-TEE due to lack of compliance. In the remaining 61 patients, a PFO was detected by c-TEE in 49 (80%) patients. Additional c-TTE study extended the examination for PFO detection to 66 patients, with a total of 57 PFO diagnosis (86%). An alternative stroke cause (i.e. an ulcerated aortic plaque) was detected in four patients. CONCLUSION: A combined ultrasound approach based on a flexible diagnostic algorithm improved our ability to detect a PFO or alternative stroke cause in patients with acute cerebral ischemia of undetermined cause and to optimize secondary stroke prevention.